Summary The skin is the outmost epithelial tissue of a body that is under frequent assaults of environmental agents. To protect against the assaults and maintain the local tissue integrity, immune cells need to be properly positioned in the skin. A group of immune cells, namely innate lymphoid cells (ILCs), are preferentially localized in the skin where they function as the first line of defense but can also contribute to the skin inflammatory diseases such as topical dermatitis and psoriasis when dysregulated. The goal of this project is to understand how the establishment of ILCs in the skin is regulated for the immune protection and homeostasis of the skin during early fetal/neonatal stages. Our preliminary study discovered a novel process that directs fetal/newborn thymic NK1.1+ ILCs to acquire a skin-homing property for their specific localization into the skin. Considering that the skin is under assaults of environmental agents immediately after the birth, we propose that the preferential generation of fetal/neonatal thymic innate lymphocytes with skin-homing properties represents a developmentally programmed process that targets innate lymphocyte populations to the skin for the ?border? protection in the neonatal stage and helps establish the immune homeostasis. In this application, we propose to dissect molecular mechanisms regulating the preferential acquisition of the skin-homing property by fetal thymic innate lymphocytes and its roles in promoting the establishment of skin immune homeostasis.